Narcolepsy with cataplexy affects 1:2,000 Americans, yet little is known about the neural pathways that control cataplexy - episodes of muscle paralysis that are often triggered by positive emotions. The neuropeptide orexin (hypocretin) clearly plays a central role in this system because people, dogs, and mice with deficient orexin signaling have narcolepsy with cataplexy. We and others have made good progress identifying the factors that regulate the activity of the orexin neurons, and we now plan to investigate how the orexin neurons suppress cataplexy. Using mouse models of narcolepsy, we will apply powerful genetic, anatomic, and physiologic techniques to define the complex neural circuits that underlie cataplexy. To determine whether mouse cataplexy is similar to that seen in people with narcolepsy, we will test whether mouse cataplexy is triggered by positive emotions and drugs known to affect human cataplexy. Next, we will define the neurochemical systems through which orexin suppresses cataplexy by studying orexin receptor knock-in mice that produce orexin receptors only in neurons producing catecholamines, serotonin, or dopamine D2 receptors. To define the brain regions through which orexin suppresses cataplexy, we will microinject an adeno-associated viral vector containing Cre recombinase into specific brainstem regions of these orexin receptor knock-in mice, thus inducing focal expression of orexin receptors and rescuing the cataplexy phenotype. Last, we will use anterograde and retrograde tracing techniques to map the neural pathways through which orexin suppresses cataplexy. By physiologically and anatomically defining the pathways through which orexin suppresses cataplexy, we will gain novel insights into the neurobiology of atonia that should lead to more effective and rational therapies for cataplexy, narcolepsy, and other disorders of motor control.